Rheumatoid arthritis (RA) is an important health problem, causing significant pain, disability and financial[unreadable] burden. Unfortunately, its etiology and pathogenesis remain enigmatic, restricting the rational choice of[unreadable] therapeutic strategies. Appreciation of a crucial role for B cells and the antibodies they produce has waxed[unreadable] and waned over the years but, of late, these players have moved back into the limelight, primarily because[unreadable] of the recent positive clinical results using anti-CD20. The K/BxN mouse model of inflammatory arthritis[unreadable] highlights the role of B cells and antibodies. Particularly convenient is an adaptation wherein transfer of[unreadable] serum from arthritic mice into normal recipients rapidly, robustly and repeatedly induces arthritis.[unreadable] Preliminary data indicate that engagement of Toll-like receptors (TLRs) by pathogen-associated molecule[unreadable] patterns can have a striking positive or negative impact on K/BxN serum-transferred arthritis. In particular,[unreadable] injection of certain CpG-containing oligodeoxynucleotides (ODNs) in either a preventive or therapeutic[unreadable] mode inhibits arthritis development or progression. This is an early effect, exerting its impact between the[unreadable] characteristic opening of the vasculature and initiation of the inflammatory cascade signaled by immune[unreadable] complex deposition, complement activation and leukocyte invasion. It requires interleukin-12p35,[unreadable] interferon (IFN)-gamma and TLR9, and also appears to depend on both natural killer and dendritic cells. The[unreadable] CpG-mediated inhibitory effect is mimicked by systemic injection of IFN-gamma. It operates in the prototypical[unreadable] C57BI/6 strain, but not in the Balb/c. Here we propose to explore the cellular and molecular mechanisms[unreadable] underlying CpG-promoted protection from K/BxN serum-transferred arthritis, and to dissect genetic[unreadable] influences on them. More specifically, we aim to: Determine how ODN1668 promotes IFN-gamma production,[unreadable] Elucidate events downstream of IFN-gamma production, Determine why Balb/c mice resist the inhibitory effect of ODN1668. An encouraging performance by recombinant human IFN-gamma in several small clinical trials on RA patients in the 1980s and 1990s suggests that results from the studies proposed may have validity in the human[unreadable] system, despite some known differences in TLR expression and downstream elements.